Large Granular Lymphocytes Leukemia Clinical Trial
— LGLOfficial title:
Prospective, Sequential Multiple Assignment, Multicentric, Phase II Randomized Controlled Trial on Two Parallel Groups Comparing the Efficacy of Two Immunosuppressive Drugs (Methotrexate, Cyclophosphamide) in Large Granular Lymphocytes Leukemia
| Verified date | February 2024 |
| Source | Rennes University Hospital |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
LGL leukemia represents a rare subtype of chronic T or NK lymphoproliferative disorders. It is an indolent disease, the main hematological or autoimmune complications lead to a treatment in more than 60% of patients. Investigators set up at the University Hospital of Rennes, a database of more than 300 patients with LGL leukemia from major French services that support this disease, and published in 2010 the largest series of patients in the world (n = 229). However, the limited heterogeneity and retrospective data collected, as all previously released, makes it difficult the proposal of consensual treatment options. If first and second line treatments are based on the use of immunosuppression with methotrexate, cyclophosphamide, or cyclosporin A, no molecule has proven superiority over others. Methotrexate and cyclophosphamide are mainly used in the first line. Invetigators just have in the literature data on about 100 patients treated with either of these drugs. Combining the results of our series with those in the literature, invetigators estimate the respective overall response rate (RG) and complete response rate (CR) in 55% and 30% for methotrexate, and 60% and 50% for cyclophosphamide. Thus, there are four objective in this study : 1. to compare the respective efficacies of methotrexate and cyclophosphamide when administered as first-line therapies in patients suffering from T/NK LGL leukemia with severe neutropenia or neutropenia associated with infections, and/or anemia requiring transfusions, and/or auto-immune associated disease 2. to evaluate the percentage of patients refractory to methotrexate or cyclophosphamide for which a second line treatment is efficacious 3. to explore, in case of non-response to the first-line therapy, the efficacy of ciclosporine A, the comparison being performed with the treatment which was not administered in the first-line therapy 4. to evaluate the response rate according to the phenotypic subtype of LGL leukemia.
| Status | Active, not recruiting |
| Enrollment | 166 |
| Est. completion date | May 26, 2027 |
| Est. primary completion date | February 5, 2024 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria: - Common criteria of LGL leukemia: the diagnosis is based on a chronic LGL peripheral blood expansion (>0.5x109/L), usually lasting more than 6 months - Specific criteria for T-LGL leukemia or NK-LGL lymphocytosis or chronic NK-LGL leukemia: - Specific criteria for T-LGL leukemia: - Expression of LGL surface markers compatible with an activated T-cell (commonly alpha-beta+/CD3+/CD8+/CD57+ and/or CD16+) phenotype or gamma-delta+ T cells; - Clonal rearrangement of TCR? gene using PCR or specific and clonal Vß expression using FCM. - Specific criteria for NK-LGL lymphocytosis or chronic NK LGL leukemia: - Expression of LGL surface markers compatible with a NK cell (commonly CD3-/CD8+/CD16+ and/or CD16+/CD56+) phenotype; - CD56+ or CD16+ NK cells greater than 0.75x109/L; - The term of chronic NK-LGL lymphocytosis is used for patients with chronic illness (NB: patients with massive tissue LGL infiltration of the spleen, liver and bone marrow and presenting aggressive clinical behavior are considered as having aggressive NK-LGL leukemia and should not be included). - Age above 18 years - ECOG performance status of 0-2 - Life expectancy of at least 1 year - Lack of previous treatment (except with G-CSF or transfusions) - At least one indication of treatment: - Isolated severe neutropenia (ANC <0.5x109/L) or neutropenia (ANC <1.5x109/L) with two or more infections requiring antibiotics; - Anemia (whatever the underlying mechanism: pure red cell aplasia or marrow infiltration) requiring transfusions greater than 2 units for two months prior to inclusion, or symptomatic anemia (hemoglobin <10g/dl) with impairment of the quality of life; - Associated complications such as systemic diseases or auto-immune diseases (i.e. recurrent uveitis, cutaneous vasculitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, rheumatoid arthritis resistant to steroids and/or immunomodulator agents (colchicin, disulone, hydrochloroquine)) and justifying a treatment with methotrexate or cyclophosphamide - Written informed consent Exclusion Criteria: - Inability to understand or to follow study procedures - Prior or concurrent malignancy within the past 5 years except inactive nonmelanomatous skin cancer or carcinoma in situ of the cervix - Other serious medical illnesses, such as hepatic, renal, cardiac, pulmonary, neurologic, or metabolic disease that would preclude the patient's ability to tolerate methotrexate, cyclophosphamide, or ciclosporine A - Reactive LGL lymphocytosis (i.e. after viral infection) - ALAT/ASAT or alkalin phosphatases >3 times normal values - Creatinine clairance <50 ml/min - Serologic evidence of HIV, hepatitis C or hepatitis B infection - Non effective contraception - Positive pregnancy test - Nursing woman |
| Country | Name | City | State |
|---|---|---|---|
| France | CHU Sud | Amiens | |
| France | CHU Angers | Angers | |
| France | Intern medecine Service - CH Antibes-Juan-les-Pins | Antibes | |
| France | Hematology Service - CH Avignon | Avignon | |
| France | Hematology Service - CH de la cote basque | Bayonne | |
| France | hematology service - CH Beauvais | Beauvais | |
| France | Hematology Service - CH Jean Minjoz | Besançon | |
| France | Hematology Service - CH Beziers | Beziers | |
| France | Hematology Unit - HOpital Avicienne | Bobigny | |
| France | Hematology Service - CH Docteur Duchenne | Boulogne sur Mer | |
| France | Hematology Service - CH de Brest | Brest | |
| France | Hematology Service - CH François Baclesse | Caen | |
| France | hematology Service - CH Louis Pasteur | Chartres | |
| France | Centre Hospitalier de Cholet | Cholet | |
| France | Hopital Inter-Armées Percy | Clamart | |
| France | hematology Service - CHU Estaing | Clermont-Ferrand | |
| France | Hematology Service - Civils hospital | Colmar | |
| France | Hematology Service CHSF | Corbeil Essonnes | |
| France | CHU Henri Mondor Lymphoid Hemopathy Unit | Creteil | |
| France | Hematology Unit CH Michalon | Grenoble | |
| France | Hematology Unit CHD Vendée | La Roche sur Yon | |
| France | Hematology Unit CH LE MANS | Le Mans | |
| France | CH Robert Boulin | Libourne | |
| France | Hematology Unit CHRU Lille | Lille | |
| France | Hematology Unit CHU Dupuytren | Limoges | |
| France | CH de Bretagne Sud | Lorient | |
| France | Hematology Unit - Institut Paoli-Calmettes | Marseille | |
| France | Hematology Unit CHU La Conception | Marseille | |
| France | Hematology Unit CH Meaux | Meaux | |
| France | Hematology Unit CH Notre Dame Bon Secours | Metz | |
| France | Hematogy Unit CHU ST ELOI | Montpellier | |
| France | Hematology Unit CH E.MULLER | Mulhouse | |
| France | Internal Medicine - CHU Hotel Dieu | Nantes | |
| France | Oncology Unit CH Antoine Lacassagne | Nice | |
| France | hematology Unit CHU Caremeau | Nimes | |
| France | Hematology Unit - CHR Orleans | Orleans | |
| France | AP-HP Hôpital Necker - Enfants Malades | Paris | |
| France | Hematology Service - Hopital La Pitié Salpetrière | Paris | |
| France | Hematology Unit - Hopital Hotel Dieu | Paris | |
| France | Hematology Unit - Hopital Saint Antoine | Paris | |
| France | Hematology Unit - Hopital Saint Louis | Paris | |
| France | Hematology Unit Hopital Saint Jean | Perpignan | |
| France | Hematology Service- CH Haut Leveque | Pessac | |
| France | Hematology Unit CH LYON SUD | Pierre Benite | |
| France | Hematology Unit CHU La Miletrie | Poitiers | |
| France | Hematology Unit CH René DUBOS | Pontoise | |
| France | CH Annecy - Hematology Service | Pringy | |
| France | Hematology Unit- Hopital Robert Debré | Reims | |
| France | Hematology Service - CHU of Rennes | Rennes | |
| France | Hematology Unit - CH Becquerel | Rouen | |
| France | Oncology Unit - Institut de cancérologie de la Loire | Saint Priest en Jarez | |
| France | CH Saint Quentin Oncohematology | Saint Quentin | |
| France | CH Yves Lefoll | Saint-Brieuc | |
| France | Hematology Unit CHU Toulouse | Toulouse | |
| France | Hematology Unit CHU Bretonneau | Tours | |
| France | Hematology Unit Hopitaux de Brabois | Vandoeuvre les Nancy | |
| France | Intern Medecine Unit CHBA | Vannes | |
| France | Hôpital André Mignot Centre Hospitalier de Versailles | Versailles |
| Lead Sponsor | Collaborator |
|---|---|
| Rennes University Hospital |
France,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Complete response (CR) | The main endpoint will be the hematological CR rate evaluated after 4 months of treatment (binary endpoint). Complete response (CR) is defined as a normalization of clinical examination (disappearance of splenomegaly) and a complete normalization of blood counts (i.e., hemoglobin >12g/dL, platelets >150x109/L, ANC >1.5x109/L), lymphocytosis <4x109/L and circulating LGL in the normal range (<0.3x109/L). The number of LGL will be quantitated on blood smears. | at Month 4 | |
| Secondary | overall response rate (ORR) | Hematological overall response rate (ORR) defined as the sum of complete responses and partial responses over the total number of patients. | at Month 4, and at Month 8 and Month 12 in non-responders at Month 4 | |
| Secondary | Complete response (CR) | Complete response (CR) is defined as a normalization of clinical examination (disappearance of splenomegaly) and a complete normalization of blood counts (i.e., hemoglobin >12g/dL, platelets >150x109/L, ANC >1.5x109/L), lymphocytosis <4x109/L and circulating LGL in the normal range (<0.3x109/L). The number of LGL will be quantitated on blood smears. | at Month 8 and Month 12 | |
| Secondary | Hematological partial response (PR) | Hematological partial response (PR) defined as an improvement in blood counts which do not meet criteria for complete remission (e.g., ANC increasing more than 50% and reaching more than 0.5 but less than 1.5x109/L with non-recurrence of infections, or hemoglobin level increasing more than 2 g/dL from baseline and transfusion requirements stopping without normalization of the hemoglobin level defined as hemoglobin >12g/dL). | at Month 4, Month 8 and Month 12 | |
| Secondary | Progressive disease | Progressive disease defined as worsening of cytopenia or organomegaly or incidence of infections. | at Month 4, Month 8 and Month 12 | |
| Secondary | Time-to-relapse | Time-to-relapse (censored variable). Relapse is defined as re-occurrence of either neutropenia or anemia (ANC <1x109/L and/or hemoglobin <10g/dL) or clonal LGL >0.5x109/L in complete responders, or as a return to baseline values of either ANC or hemoglobin in partial responders, at two monthly consecutive blood tests. | from Month 4 to endpoint (in first-line treatment responders) | |
| Secondary | Time-to-relapse | Time-to-relapse (censored variable). Relapse is defined as re-occurrence of either neutropenia or anemia (ANC <1x109/L and/or hemoglobin <10g/dL) or clonal LGL >0.5x109/L in complete responders, or as a return to baseline values of either ANC or hemoglobin in partial responders, at two monthly consecutive blood tests. | from Month 8 to endpoint (in second-line treatment responders) | |
| Secondary | Molecular remission | Molecular remission defined as the disappearance of the clonal pattern of TCR gamma multiplex rearrangement and Phenotypic remission is defined as :
For the T subtype: disappearance of the excess of CD3+/CD8+ cells (or disappearance of the LGL clone according to the specific subtype observed at inclusion); For the NK subtype: disappearance of the excess of CD3-/CD56+ cells (or disappearance of the LGL clone according to the specific subtype observed at inclusion) |
at Month 4 and Month 12 for hematological complete responders | |
| Secondary | Adverse events rate | Adverse events rate | Month 2, Month 4, Month 6, Month 8, Month 10, Month 12 | |
| Secondary | Compliance | Compliance | Month 2, Month 4, Month 6, Month 8, Month 10, Month 12 | |
| Secondary | relationship between the response to treatment and the phenotypic subtype | Identification of a relationship between the response to treatment and the phenotypic subtype characterized by the panel of monoclonal antibodies defined in the ancillary study subsection. | Day 1 |